Treatment of progressive neurodegenerative disease with ibudilast

ABSTRACT

Compositions and methods for treating progressive neurodegenerative diseases, and their associated symptoms by administration of ibudilast (3-isobutyryl-2-isopropylpyrazolo[1,5-a]pyridine).

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/078,291, filed Mar. 23, 2016, which is a continuation of U.S. patentapplication Ser. No. 14/188,061, filed Feb. 24, 2014; now U.S. Pat. No.9,314,452, which is a continuation of U.S. patent application Ser. No.13/725,627, filed Dec. 21, 2012; now U.S. Pat. No. 9,114,136, which is acontinuation of U.S. patent application Ser. No. 13/402,702, filed Feb.22, 2012; now U.S. Pat. No. 8,338,453, which is a continuation of U.S.patent application Ser. No. 12/169,042, filed Jul. 8, 2008; now U.S.Pat. No. 8,138,201, which claims the benefit of U.S. Provisional PatentApplication No. 60/929,745, filed Jul. 11, 2007, and U.S. ProvisionalPatent Application No. 61/042,181, filed Apr. 3, 2008. The contents ofthese applications are incorporated herein by reference in theirentirety.

FIELD OF THE INVENTION

The present invention relates generally to methods for treatingprogressive neurodegenerative diseases. In particular, the presentinvention pertains to methods of treating or preventing progressiveneurodegenerative diseases and their associated symptoms byadministration of ibudilast(3-isobutyryl-2-isopropylpyrazolo[1,5-a]pyridine).

BACKGROUND OF THE INVENTION

The small molecule ibudilast(3-isobutyryl-2-isopropylpyrazolo[1,5-a]pyridine) is a selectiveinhibitor of cyclic nucleotide phosphodiesterases (PDEs) 3A, 4, 10A1 and11A1 (Gibson et al., Eur J Pharmacol 538: 39-42, 2006). Ibudilast alsoacts as a leukotriene D4 antagonist, an anti-inflammatory, a PAFantagonist, and a vasodilatory agent (Thompson Current Drug Reports).Ibudilast is thought to exert a neuroprotective role in the centralnervous system of mammals, presumably via suppression of the activationof glial cells (Mizuno et al., Neuropharmacology 46: 404-411, 2004).

Ibudilast has been widely used in Japan for relieving symptomsassociated with ischemic stroke or bronchial asthma. In recent clinicaltrials, its use in the treatment of multiple sclerosis (MS), aninflammatory disease of the central nervous system, has been explored(News.Medical.Net; Pharmaceutical News, 2 Aug. 2005). As disclosed inthis publication, this clinical trial was expected to treat“relapsing-remitting MS,” however, no mention is made of progressivemultiple sclerosis. In U.S. Pat. No. 6,395,747, ibudilast is disclosedas a treatment for multiple sclerosis, which is generally understood tomean relapsing and remitting multiple sclerosis, not progressivemultiple sclerosis. US Patent Application No. 20060160843 disclosesibudilast for the treatment of intermittent and short term pain,however, this is not pain related to a progressive neurodegenerativedisease.

While the use of ibudilast for a number of varying indications has beenreported to date, to the best of the applicants' knowledge, its use intreating progressive neurodegenerative diseases has heretofore remainedlargely unexplored.

SUMMARY OF THE INVENTION

The present invention relates to a novel approach to treatingprogressive neurodegenerative diseases and is based upon the surprisingdiscovery that progressive neurodegenerative diseases can besuccessfully treated or prevented by administration of ibudilast. Usingstandard progressive neurodegenerative diseases models, the inventorshave discovered that the systemic administration of ibudilast iseffective in preventing and/or attenuating, if not eliminating, chronicprogressive neurodegenerative diseases, such as that associated withvarious syndromes.

Accordingly, in one aspect, the invention provides a method of treatinga human subject suffering from a progressive neurodegenerative diseaseby administering to the subject a therapeutically effective amount ofibudilast.

Human subjects suitable to be selected for treatment include thosesuffering from dementia absent other prominent neurologic signs,Alzheimer's disease, Senile dementia of the Alzheimer type, or Pick'sdisease (lobar atrophy), neurodegenerative diseases that includesyndromes combining progressive dementia with other prominent neurologicabnormalities, progressive neurodegenerative disease mainly afflictingadults and including progressive neurodegenerative forms of Huntington'sdisease, multiple system atrophy combining dementia with ataxia and/ormanifestation of Parkinson's disease, progressive supranuclear palsy(Steele-Richardson-Olszewski), diffuse Lewy body disease, orcorticodentatinigral degeneration. Additional subjects can be sufferingfrom progressive neurodegenerative disease that mainly afflicts youngadults and children and include Hallervorden-Spatz disease andprogressive familial myoclonic epilepsy, progressive neurodegenerativedisease that includes syndromes of gradually developing abnormalities ofposture and movement, or disease that includes paralysis agitans(Parkinson's disease), striatonigral degeneration, progressivesupranuclear palsy, torsion dystonia (torsion spasm; dystonia musculorumdeformans), spasmodic torticollis and other restricted dyskinesias,Familial tremor, or Gilles de la Tourette syndrome, syndromes ofprogressive ataxia, cerebellar degenerations or spinocerebellardegenerations, cerebellar cortical degeneration or olivopontocerebellaratrophy (OPCA), spinocerebellar degenerations including spinocerebellardegenerations (Friedreich's ataxia and related disorders). Otherindications include central autonomic nervous system failure (Shy-Dragersyndrome), syndromes of muscular weakness and wasting without sensorychanges (motor neuron disease), amyotrophic lateral sclerosis (ALS),spinal muscular atrophy, infantile spinal muscular atrophy(Werdnig-Hoffmann), juvenile spinal muscular atrophy(Wohlfart-Kugelberg-Welander), or other forms of familial spinalmuscular atrophy, primary lateral sclerosis or hereditary spasticparaplegia, syndromes combining muscular weakness and wasting withsensory changes (progressive neural muscular atrophy; chronic familialpolyneuropathies), peroneal muscular atrophy (Charcot-Marie-Tooth),hypertrophic interstitial polyneuropathy (Deferine-Sottas), ormiscellaneous forms of chronic progressive neuropathy, progressiveneurodegenerative diseases that include syndromes of progressive visualloss. Other indications treatable with the present invention arepigmentary degeneration of the retina (retinitis pigmentosa), orhereditary optic atrophy (Leber's disease), motor neuron disease and theprogressive ataxias; sporadic progressive neurodegenerative diseases,multifocal motor neuropathy with conduction block, motor neuropathy withparaproeinemia, motor-predominant peripheral neuropathies,olivopontocerebellar atrophy, Azorean (Machado-Joseph) disease, familialprogressive neurodegenerative diseases such as familial amyotrophiclateral sclerosis, spinal muscular atrophies, familial spasticparaparesis, hereditary biochemical disorders, arthrogryposis muliplexcongenital, or progressive juvenile bulbar palsy (Fazio-Londe)—Examplesof hereditary biochemical disorders are superoxide dismutase deficieny,hexosaminidase A and B deficiency, or androgen receptor mutation(Kennedy's syndrome). Furthermore, progressive neurodegenerativediseases can include viral and prion diseases, such as HTLV-1 associatedmyelopathy, progressive multifocal leukoencephalopathy,Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker disease, kuru,fatal familial insomnia, or Alper's disease.

In one or more alternative embodiments of the method, ibudilast isadministered at a daily dosage amount ranging from about 30 mg to 240 mgdaily, or from about 30 mg to 180 mg daily, 60 mg to 120 mg daily, or 20to 80 mg daily.

The therapeutic dosage amount may be achieved by administration oncedaily (i.e., in a single dose), twice daily (i.e., in two separatedoses), three times daily, or may be administered as multiple doses overa time course of several days, weeks, or even months. Such administeringis typically over a duration of time effective to result in a slowing(an inhibition) or dimunition (a lessening), and ideally elimination oreven reversal, of a progressive neurodegenerative disease. Exemplarydurations of treatment include at least about 1 month, from 1 to 3months, up to about 6 months, up to about 12 months or even longer, suchas 24 months or longer. In one particular embodiment, treatment lastsfrom about 1 week to about 52 weeks.

In a preferred embodiment of the treatment method, the administering isover a duration of time effective to result in elimination of theprogressive neurodegenerative disease. Such a time can be a least oneyear, for at least 20 months or for at least two years.

In a specific embodiment of the invention, a method is described inwhich an effective amount of ibudilast is administered to patientssuffering from a progressive form of relapse remitting multiplesclerosis (RRMS) patients, who are at risk for conversion of theirdisease to secondary progressive multiple sclerosis (SPMS), whereby therate of conversion from RRMS to SPMS is decreased by at leastapproximately half for such patients who are treated daily with aneffective amount of ibudilast for a period of at least two years(compared, for example, to untreated patients or to patients treateddaily for only one year). Thus, the present method includes a method ofadministering effective amounts of ibudilast to certain patientpopulations for at least about two years, at least about three years, atleast about four years, or at least about five years and perhaps longer.

In yet another embodiment, ibudilast, when administered either singly oras part of a combination therapy, is administered either systemically orcentrally (e.g., by intrathecal administration, i.e., into thecerebrospinal fluid surrounding the spinal cord). Such administration ofibudilast provides a novel mechanism to attenuate progressiveneurodegenerative diseases, potentially via suppression of glialactivation.

According to yet a further embodiment, ibudilast is administeredsystemically, e.g. via parenteral, enteral, oral, intravenous,intranasal, sublingual or other systemic routes, to a human, subject forthe treatment of progressive neurodegenerative diseases.

In another aspect, the invention provides a composition or combinationeffective for treating progressive neurodegenerative diseases. Thecomposition comprises a combination of: (i) ibudilast, and (ii) at leastone additional agent effective for treating progressiveneurodegenerative diseases, where each of the components is eithercontained in a single composition or dosage form (such as in anadmixture), or is present as a discrete or separate entity (e.g., in akit).

A composition of the invention may optionally include one or morepharmaceutically acceptable excipients.

In yet another aspect, the invention encompasses a kit comprising acombination of medicaments for the treatment of progressiveneurodegenerative diseases or a related syndrome, comprising, (i)ibudilast, and (ii) at least one additional agent effective for treatingprogressive neurodegenerative diseases, for simultaneous, sequential orseparate use.

Each of the herein-described features of the invention is meant to applyequally to each and every embodiment as described herein, unlessotherwise indicated.

Additional objects, advantages and novel features of the invention willbe set forth in the description that follows, and in part, will becomeapparent to those skilled in the art upon reading the following, or maybe learned by practice of the invention.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows the percent change in brain volume of patients in a PhaseII clinical trial. Patients being administered 60 mg a day of ibudilasthad an average of 0.79% loss of brain volume, whereas patients beinggiven a placebo had a brain volume loss of 1.2% over a 1-year treatmentperiod. This is a statistically significant result with a p value of0.0352.

FIG. 2 shows a significant reduction in brain volume loss (p=0.04), asmeasured by cranial magnetic resonance imaging (MRI) scans, observedafter 12 months in MS patients treated with 60 mg per day of MN-166compared to placebo. A similar effect was observed in therelapsing-remitting patients.

FIG. 3 shows results from a clinical trial in which patients whoreceived placebo during the first 12 months of the trial were randomizedto receive either 30 or 60 mg of MN-166 per day (double-blindmaintained) during the second 12 months of the trial; patients whoreceived 30 or 60 mg of MN-166 per day during the first 12 monthsremained on the assigned dose for the second 12 months of the trial. Theresults of the trial showed that the significant reduction in brainvolume loss (p=0.04), as measured by cranial magnetic resonance imaging(MRI) scans, observed after 12 months in patients treated with 60 mg perday of MN-166 compared to placebo (FIG. 2) was again demonstrated inYear 2 and was significantly less (p=0.030) in patients receiving 60 mgper day of MN-166 for 24 months compared to the other treatment groups(placebo for 12 months, 30 mg MN-166 for 12 months; placebo for 12months, 60 mg MN-166 for 12 months; 30 mg for 24 months).

DETAILED DESCRIPTION OF THE INVENTION

The practice of the present invention will employ, unless otherwiseindicated, conventional methods of chemistry, biochemistry, andpharmacology, within the skill of the art. Such techniques are explainedfully in the literature. See, e.g.; A. L. Lehninger, Biochemistry (WorthPublishers, Inc., current addition); Morrison and Boyd, OrganicChemistry (Allyn and Bacon, Inc., current addition); J. March, AdvancedOrganic Chemistry (McGraw Hill, current addition); Remington: TheScience and Practice of Pharmacy, A. Gennaro, Ed., 20th Ed.; FDA'sOrange Book, Goodman & Gilman The Pharmacological Basis of Therapeutics,J. Griffith Hardman, L. L. Limbird, A. Gilman, 11th Ed., 2005, The MerckManual, 18th edition, 2007, and The Merck Manual of Medical Information2003.

All publications cited herein, including internet articles, the FDAOrange Book (available on the FDA's website), books, handbooks, journalarticles, patents and patent applications, whether supra or infra, arehereby incorporated by reference in their entirety.

DEFINITIONS

Before describing the present invention in detail, it is to beunderstood that this invention is not limited to particularadministration modes, patient populations, and the like, as such mayvary, as will be apparent from the accompanying description and figures.

It must be noted that, as used in this specification and the intendedclaims, the singular forms “a,” “an,” and “the” include plural referentsunless the context clearly dictates otherwise. Thus, for example,reference to “a drug” includes a single drug as well as two or more ofthe same or different drugs, reference to “an optional excipient” refersto a single optional excipient as well as two or more of the same ordifferent optional excipients, and the like.

In describing and claiming the present invention, the followingterminology will be used in accordance with the definitions describedbelow.

“Pharmaceutically acceptable excipient or carrier” refers to anexcipient that may optionally be included in the compositions of theinvention and that causes no significant adverse toxicological effectsto the patient.

“Pharmaceutically acceptable salt” includes, but is not limited to,amino acid salts, salts prepared with inorganic acids, such as chloride,sulfate, phosphate, diphosphate, bromide, and nitrate salts, or saltsprepared from the corresponding inorganic acid form of any of thepreceding, e.g., hydrochloride, etc., or salts prepared with an organicacid, such as malate, maleate, fumarate, tartrate, succinate,ethylsuccinate, citrate, acetate, lactate, methanesulfonate, benzoate,ascorbate, para-toluenesulfonate, palmoate, salicylate and stearate, aswell as estolate, gluceptate and lactobionate salts. Similarly saltscontaining pharmaceutically acceptable cations include, but are notlimited to, sodium, potassium, calcium, aluminum, lithium, and ammonium(including substituted ammonium).

“Active molecule” or “active agent” as described herein includes anyagent, drug, compound, composition of matter or mixture which providessome pharmacologic, often beneficial, effect that can be demonstratedin-vivo or in vitro. This includes foods, food supplements, nutrients,nutriceuticals, drugs, vaccines, antibodies, vitamins, and otherbeneficial agents. As used herein, the terms further include anyphysiologically or pharmacologically active substance that produces alocalized or systemic effect in a patient.

“Substantially” or “essentially” means nearly totally or completely, forinstance, 95% or greater of some given quantity.

“Optional” or “optionally” means that the subsequently describedcircumstance may or may not occur, so that the description includesinstances where the circumstance occurs and instances where it does not.

By “progressive neurodegenerative disease” means any neurodegenerativedisease that is in the progressive state, or has progressivecharacteristics and is not solely in the state relapse and or remittingoccurrences. A progressive state is a worsening of symptoms over time.Generally, the symptoms worsen at a gradual rate.

Examples of progressive neurodegenerative diseases include Alzheimer'sDisease, Parkinsonism and amyotrophic lateral sclerosis.

The term “central nervous system” or “CNS” includes all cells and tissueof the brain and spinal cord of a vertebrate. Thus, the term includes,but is not limited to, neuronal cells, glial cells, astrocytes,cerebrospinal fluid (CSF), interstitial spaces and the like.

“Glial cells” refer to various cells of the CNS also known as microglia,astrocytes, and oligodendrocytes.

The terms “subject”, “individual” or “patient” are used interchangeablyherein and refer to a vertebrate, preferably a mammal. Mammals include,but are not limited to, murines, rodents, simians, humans, farm animals,sport animals and pets.

The terms “pharmacologically effective amount” or “therapeuticallyeffective amount” of a composition or agent, as provided herein, referto a nontoxic but sufficient amount of the composition or agent toprovide the desired response, such as a reduction or reversal ofprogressive neurodegenerative diseases. The exact amount required willvary from subject to subject, depending on the species, age, and generalcondition of the subject, the severity of the condition being treated,the particular drug or drugs employed, mode of administration, and thelike. An appropriate “effective” amount in any individual case may bedetermined by one of ordinary skill in the art using routineexperimentation, based upon the information provided herein.

The term “about”, particularly in reference to a given quantity, ismeant to encompass deviations of plus or minus five percent.

“Progressive neurodegenerative disease” means any neurodegenerativedisease that is in the progressive state (that is, getting worsecompared to a baseline level) or has such progressive characteristics.Thus a progressive state is a worsening of symptoms over time and can beprecipitous or gradual. Examples of progressive neurodegenerativediseases include Parkinson's disease, amyotrophic lateral sclerosis,Alzheimer's disease, and progressive forms of multiple sclerosisexclusive of relapse/remitting multiple sclerosis.

There are four recognized types of multiple sclerosis: (1)Relapsing/Remitting Multiple Sclerosis (RR multiple sclerosis), (2)Secondary Progressive Multiple Sclerosis (SP multiple sclerosis), (3)Progressive Relapsing Multiple Sclerosis (PR multiple sclerosis), and(4) Primary Progressive Multiple Sclerosis (PP multiple sclerosis). RRmultiple sclerosis is not considered to fall within the scope of theclaims, but the other forms of multiple sclerosis, i.e. SP multiplesclerosis, PR multiple sclerosis and PP multiple sclerosis areconsidered to be one aspect of the present invention. In all types ofprogressive MS, there is a loss of function over time regardless ofrelapses.

“Relapsing/Remitting Multiple Sclerosis (RR multiple sclerosis)” ischaracterized by relapses (also known as exacerbations) during whichtime new symptoms can appear and old ones resurface or worsen. Therelapses are followed by periods of remission, during which time theperson fully or partially recovers from the deficits acquired during therelapse. Relapses can last for days, weeks or months and recovery can beslow and gradual or almost instantaneous. The vast majority of peoplepresenting with Multiple Sclerosis are first diagnosed withrelapsing/remitting. This is typically when they are in their twentiesor thirties, though diagnoses much earlier or later are known. Aroundtwice as many women as men present with this variety.

In “Secondary Progressive Multiple Sclerosis (SP multiple sclerosis),” aperson who initially had relapsing-remitting multiple sclerosis beginsto develop a gradual deterioration in nerve function, with or withoutrelapses. After a number of years many people who have hadrelapsing/remitting multiple sclerosis will pass into a secondaryprogressive phase of the disease. This is characterized by a gradualworsening of the disease between relapses. In the early phases ofSecondary Progressive, the person may still experience a few relapsesbut after a while these merge into a general progression. People oftendo not return to their prior level of function after a relapse. Peoplewith secondary progressive may experience good and bad days or weeks,but, apart from some remission following relapsing episodes, have noreal recovery. After 10 years, 50% of people with relapsing/remittingmultiple sclerosis will have developed secondary progressive. By 25 to30 years, that figure will have risen to 90%.

“Progressive Relapsing Multiple Sclerosis (PR multiple sclerosis)” showsclear progression in the level of disability from the time symptomsfirst begin, but with episodes of clear relapses that may or may not beassociated with some recovery following the acute episode. This form ofmultiple sclerosis follows a progressive course from onset, punctuatedby relapses. There is significant recovery immediately following arelapse but between relapses there is a gradual worsening of symptoms.

“Primary Progressive Multiple Sclerosis (PP multiple sclerosis)” ischaracterized by a gradual progression of the disease from its onsetwith no remissions or relapses at all. There may be periods of aleveling off of disease activity and, as with secondary progressive,there may be good and bad days or weeks. PP multiple sclerosis differsfrom Relapsing/Remitting and Secondary Progressive in that onset istypically in the late thirties or early forties, men are as likely womento develop it and initial disease activity is in the spinal cord and notin the brain. Primary Progressive multiple sclerosis often migrates intothe brain, but is less likely to damage brain areas thanrelapsing/remitting or secondary progressive—for example, people withPrimary Progressive are less likely to develop cognitive problems.

“Treatment” or “treating” progressive neurodegenerative diseasesincludes arresting the development or reversing the symptom of aprogressive neurodegenerative disease.

“Persistent neuronal or axon damage” includes damage to neurons that islong term or permanent, such as when neurons die and disappear.

“Persistent black hole” is defined as a hypointense lesion. Black holes,or dark areas on a T1 weighted magnetic resonance imaging (MRI) scan,show loss of myelin and loss of axons. As one of skill in the art willappreciate, a T1 weighted scan uses longitudinal relaxation time a shortrelaxation time (TR) and short echo time (TE) (TR<1000 msec, TE<30msec).

Ibudilast

The methods of the invention for the treatment of progressiveneurodegenerative diseases are based upon administration of themolecule, ibudilast. Ibudilast is a small molecule drug (molecularweight of 230.3) having the structure shown below.

Ibudilast is also found under ChemBank ID 3227, CAS #50847-11-5, andBeilstein Handbook Reference No. 5-24-03-00396. Its molecular formulacorresponds to C₁₄H₁₈N₂O. Ibudilast is also known by various chemicalnames including2-methyl-1-(2-(1-methylethyl)pyrazolo(1,5-a)pyridin-3-yl)1-propanone;3-isobutyryl-2-isopropylpyrazolo(1,5-a)pyridine]; and1-(2-isopropyl-pyrazolo[1,5-a]pyridin-3-yl)-2-methyl-propan-1-one. Othersynonyms for ibudilast include Ibudilastum (Latin), BRN 0656579, KC-404,and MN-166. Its brand name is Ketas®. Ibudilast, as referred to herein,is meant to include any and all pharmaceutically acceptable salt formsthereof, prodrug forms (e.g., the corresponding ketal), solvates, andthe like, as appropriate for use in its intended formulation foradministration.

Ibudilast is a is a selective inhibitor of cyclic nucleotidephosphodiesterases (PDEs) 3A, 4, 10A1 and 11A1 (Gibson et al., Eur JPharmacol 538: 39-42, 2006), and has also been reported to haveleukotriene D4 and PAF antagonistic activities. Its profile appearseffectively anti-inflammatory and unique in comparison to other PDEinhibitors and anti-inflammatory agents. PDEs catalyze the hydrolysis ofthe phosphoester bond on the 3′-carbon to yield the corresponding5′-nucleotide monophosphate. Thus, they regulate the cellularconcentrations of cyclic nucleotides. Since extracellular receptors formany hormones and neurotransmitters utilize cyclic nucleotides as secondmessengers, the PDEs also regulate cellular responses to theseextracellular signals. There are at least eight classes of PDEs:Ca₂+/calmodulin-dependent PDEs (PDE1); cGMP-stimulated PDEs (PDE2);cGMP-inhibited PDEs (PDE3); cAMP-specific PDEs (PDE4); cGMP-binding PDEs(PDE5); photoreceptor PDEs (PDE6); high affinity, cAMP-specific PDEs(PDE7); and high affinity cGMP-specific PDEs (PDE9). Ibudilast acts tosuppress inflammation via action on inflammatory cells (e.g., glialcells) resulting in the suppression of both pro-inflammatory mediatorand neuroactive mediator release. Ibudilast may also suppress theproduction of pro-inflammatory cytokines (IL-1β, TNF-α) and may enhancethe production of the anti-inflammatory cytokines (IL-4, IL-10).References related to the foregoing include the following: Obernolte,R., et al. (1993) “The cDNA of a human lymphocyte cyclic-AMPphosphodiesterase (PDE IV) reveals a multigene family” Gene 129:239-247; Rile, G., et al. (2001) “Potentiation of ibudilast inhibitionof platelet aggregation in the presence of endothelial cells” Thromb.Res. 102: 239-246; Souness, J. E., et al. (1994) “Possible role ofcyclic AMP phosphodiesterases in the actions of ibudilast on eosinophilthromboxane generation and airways smooth muscle tone” Br. J. Pharmacol.111: 1081-1088; Suzumura, A., et al. (1999) “Ibudilast suppressesTNF.alpha. production by glial cells functioning mainly as type IIIphosphodiesterase inhibitor in CNS” Brain Res. 837: 203-212; Takuma, K.,et al. (2001) “Ibudilast attenuates astrocyte apoptosis via cyclic GMPsignaling pathway in an in vitro reperfusion model” Br. J. Pharmacol.133: 841-848.

As stated previously, a reference to any one or more of theherein-described drugs, in particular ibudilast, is meant to encompass,where applicable, any and all enantiomers, mixtures of enantiomersincluding racemic mixtures, prodrugs, pharmaceutically acceptable saltforms, hydrates (e.g., monohydrates, dihydrates, etc.), solvates,different physical forms (e.g., crystalline solids, amorphous solids),metabolites, and the like.

Method of Administration

As set forth above, the present invention is directed to a method oftreating a human subject suffering from a progressive neurodegenerativedisease by administering a therapeutically effective dosage ofibudilast. Such administering is effective to decrease the amount ofprogressive neurodegenerative disease experienced by the subject, i.e.,to result in a significant attenuation or even reversal of progressiveneurodegenerative disease, as demonstrated in the accompanying Examples.Ibudilast is preferably administered at a daily dosage amount rangingfrom about 30 mg to 240 mg daily, or from about 30 mg to 180 mg daily,or 60 mg to 120 mg daily.

The method of the invention may, in certain instances, comprise a stepof selecting a subject experiencing progressive neurodegenerativediseases prior to administering ibudilast thereto. Such subjects aretypically selected from those suffering from: Alzheimer's disease,Senile dementia of the Alzheimer type, or Pick's disease (lobaratrophy), syndromes combining progressive dementia with other prominentneurologic abnormalities, Huntington's disease, multiple system atrophycombining dementia with ataxia and/or manifestation of Parkinson'sdisease, progressive supranuclear palsy (Steele-Richardson-Olszewski),diffuse Lewy body disease, or corticodentatinigral degeneration,Hallervorden-Spatz disease and progressive familial myoclonic epilepsy,symptoms of gradually developing abnormalities of posture and movement,paralysis agitans (Parkinson's disease), striatonigral degeneration,progressive supranuclear palsy, torsion dystonia (torsion spasm;dystonia musculorum deformans), spasmodic torticollis and otherrestricted dyskinesias, Familial tremor, or Gilles de la Tourettesyndrome, progressive ataxia, cerebellar degenerations orspinocerebellar degenerations, cerebellar cortical degeneration orolivopontocerebellar atrophy (OPCA), spinocerebellar degenerations(Friedreich's ataxia and related disorders), central autonomic nervoussystem failure (Shy-Drager syndrome), syndromes of muscular weakness andwasting without sensory changes (motor neuron disease), amyotrophiclateral sclerosis (ALS), spinal muscular atrophy, infantile spinalmuscular atrophy (Werdnig-Hoffmann), juvenile spinal muscular atrophy(Wohlfart-Kugelberg-Welander), or other forms of familial spinalmuscular atrophy, primary lateral sclerosis, or hereditary spasticparaplegia, syndromes combining muscular weakness and wasting withsensory changes (progressive neural muscular atrophy; chronic familialpolyneuropathies), peroneal muscular atrophy (Charcot-Marie-Tooth),hypertrophic interstitial polyneuropathy (Deferine-Sottas), ormiscellaneous forms of chronic progressive neuropathy, syndromes ofprogressive visual loss, pigmentary degeneration of the retina(retinitis pigmentosa), or hereditary optic atrophy (Leber's disease),Parkinson's disease and other extrapyramidal disorders, progressivesupranuclear palsy (Steele-Richardson-Olszewski syndrome), torsiondystonia (torsion spasm, dystonia musculorum deformans), focaldystonias, Familial tremors, or Gilles de la Tourette syndrome, motorneuron disease and the progressive ataxias, amyotrophic lateralsclerosis, primary lateral sclerosis, multifocal motor neuropathy withconduction block, motor neuropathy with paraproeinemia,motor-predominant peripheral neuropathies, olivopontocerebellar atrophy,Azorean (Machado-Joseph) disease, familial progressive neurodegenerativediseases, familial amyotrophic lateral sclerosis, spinal muscularatrophies, familial spastic paraparesis, hereditary biochemicaldisorders, arthrogryposis muliplex congenital, or progressive juvenilebulbar palsy (Fazio-Londe), infantile (Werdnig-Hoffman disease),childhood onset, or adolescent (Wohlfart-Kugelberg-Welander disease),familial HTLV-1 myelopathy, isolated FSP, or complicated FSP, superoxidedismutase deficiency, hexosaminidase A and B deficiency, or androgenreceptor mutation (Kennedy's syndrome), viral and prion diseases,myelopathy, progressive multifocal leukoencephalopathy,Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker disease, kuru,fatal familial insomnia, or Alper's disease, includes primaryprogressive or secondary progressive multiple sclerosis, but excludesrelapsing, remitting multiple sclerosis, frontotemporal dementia,Wilson's disease, progressive neuropathic pain. In some embodiments ofthis invention, administering to treat patients with multiple sclerosisis excluded.

Ibudilast may also be administered in combination with an additionalagent effective for treating progressive neurodegenerative diseases. Ina preferred embodiment, such agent possesses a mechanism of actiondifferent from ibudilast. Exemplary agents include cholinesteraseinhibitors (e.g., Razadyne® (formerly known as Reminyl®) (galantamine),Exelon® (rivastigmine), Aricept® (donepezil), and Cognex® (tacrine)),N-methyl-D-aspartate (NMDA) inhibitors (e.g., Namenda® (memantine)),levodopa preparations (e.g., levodopa/carbidopa (Sinemet® or Atamet®),levodopa/benserazide (Madopar®), levodopa/carbiopa (Sinemet CR®),levodopa/benserazide (Madopar HBS®), carbidopa/levodopa/entacapone(Stalevo®)), catechol-O-methyl transferase (COMT) inhibitors (e.g.,entacapone (Comtan®), tolcapone (Tasmar®)), dopamine agonists (e.g.,bromocriptine (Parlodel®), pergolide (Permax®), pramipexole (Mirapex®),ropinirole (Requip®), cabergoline (Dostinex®), apomorphine (Apokyn®),lisuride (Dopergine®)), immunomodulating drugs (e.g., interferon beta-la(Avonex®, Rebif®), interferon beta-1b (Betaseron®), glatiramer acetate(Copaxone®), natalizumab (Tysabri®)), immunosuppressant/chemotherapydrugs (e.g, mitoxantrone (Novantrone®), azathioprine (Imuran®),cladribine (Leustatin®), cyclophosphamide (Cytoxan®), cyclosporine-A,methotrexate), oral medications for relapsing-remitting multiplesclerosis (fingolimod (FTY720), BG12, laquinimod, teriflunomide), etc.

Preferred methods of delivery of ibudilast-based therapeuticformulations for the treatment of progressive neuropathic diseasesinclude systemic and localized delivery. Such routes of administrationinclude but are not limited to, oral, intra-arterial, intrathecal,intraspinal, intramuscular, intraperitoneal, intranasal, and inhalationroutes.

More particularly, an ibudilast-based formulation of the presentinvention may be administered for therapy by any suitable route,including without limitation, oral, rectal, nasal, topical (includingtransdermal, aerosol, buccal and sublingual), vaginal, parenteral(including subcutaneous, intravenous, intramuscular, and intradermal),intrathecal, and pulmonary. The preferred route will, of course, varywith the condition and age of the recipient, the particular syndromebeing treated, and the specific combination of drugs employed.

An ibudilast composition of the invention, when comprising more than oneactive agent, may be administered as a single combination compositioncomprising a combination of ibudilast and at least one additional activeagent effective in the treatment of progressive neurodegenerativediseases. In terms of patient compliance and ease of administration,such an approach is preferred, since patients are often adverse totaking multiple pills or dosage forms, often multiple times daily, overthe duration of treatment. Alternatively, albeit less preferably, thecombination of the invention is administered as separate dosage forms.In instances in which the drugs comprising the therapeutic compositionof the invention are administered as separate dosage forms andco-administration is required, ibudilast and each of the additionalactive agents may be administered simultaneously, sequentially in anyorder, or separately.

Dosages

Therapeutic amounts can be empirically determined and will vary with theparticular condition being treated, the subject, and the efficacy andtoxicity of each of the active agents contained in the composition. Theactual dose to be administered will vary depending upon the age, weight,and general condition of the subject as well as the severity of thecondition being treated, the judgment of the health care professional,and particular combination being administered.

Therapeutically effective amounts can be determined by those skilled inthe art, and will be adjusted to the requirements of each particularcase. Generally, a therapeutically effective amount of ibudilast willrange from a total daily dosage of about 0.1 and 200 mg/day, morepreferably, in an amount between 1-240 mg/day, 30-240 mg/day, 1-120mg/day, 30-120 mg/day, administered as either a single dosage or asmultiple dosages. Preferred dosage amounts include dosages greater thanabout 10 mg BID or TID. That is to say, a preferred dosage amount isgreater than about 20 mg/day or greater than 30 mg/day. Dosage amountsmay be selected from 30 mg/day, 60 mg/day, 90 mg/day or 120 mg/day ormore. Depending upon the dosage amount and precise condition to betreated, administration can be one, two, or three times daily for a timecourse of one day to several days, weeks, months, and even years, andmay even be for the life of the patient. Illustrative dosing regimeswill last a period of at least about a week, from about 1-4 weeks, from1-3 months, from 1-6 months, from 1-52 weeks, from 1-24 months, orlonger.

Practically speaking, a unit dose of any given composition of theinvention or active agent can be administered in a variety of dosingschedules, depending on the judgment of the clinician, needs of thepatient, and so forth. The specific dosing schedule will be known bythose of ordinary skill in the art or can be determined experimentallyusing routine methods. Exemplary dosing schedules include, withoutlimitation, administration five times a day, four times a day, threetimes a day, twice daily, once daily, every other day, three timesweekly, twice weekly, once weekly, twice monthly, once monthly, and soforth.

Approaches for Treatment of Progressive Neurodegenerative Diseases

Ibudilast is a potent suppressor of glial activation (Mizuno et al.(2004) Neuropharmacology 46: 404-411). In a dose-dependent manner,ibudilast has been shown to suppress the production of nitric oxide(NO), reactive oxygen species, interleukin (IL)-1.beta., IL-6, and tumornecrosis factor (TNF) and enhance the production of the inhibitorycytokine, IL-10, along with additional neurotrophic factors includingnerve growth factor (NGF), glia-derived neurotrophic factor (GDNF), andneurotrophin (NT)-4 in activated microglia. Thus,ibudilast-mediated-neuroprotection was found to be primarily due to theinhibition of inflammatory mediators and the upregulation ofneurotrophic factors.

Ibudilast crosses the blood-brain barrier when administered systemically(Sugiyama et al. (1993) No To Shinkei 45(2):139-42; FIG. 5), thuseliminating the need for more invasive methods of administration inorder to access central sites of progressive neurodegenerative diseases.

As shown in Example 1, the inventors of the present invention made thesurprising discovery in a human clinical trial that administration ofibudilast can reduce brain volume loss in patients that are sufferingfrom an affliction that causes brain volume to shrink. Without wishingto be bound by a particular theory, the present inventors believe thatibudilast administered in accordance with the present claims will causea slowing or reversal in the loss of brain volume due to the atropy anddeath of neurons in a progressive neurodegenerative disease that causesthe brain to shrink; these changes can be tracked in cerebral MR or CTimages. This discovery of the slowing or reversal of brain volumeshrinkage has significant application in the treatment of progressiveneurodegenerative diseases described in this application.

Animal Models

The ability of ibudilast to treat progressive neuropathic diseases canbe evaluated by any of the standard progressive neuropathic diseasemodels known in the art. Examples of such models are described in AnimalModels of Neurological Disease: Neurodegenerative Diseases(Neuromethods) by Alan A. Boulton, Glen B. Baker, and Roger F.Butterworth (1992); Handbook of Laboratory Animal Science, SecondEdition: Volumes I-III (Handbook of Laboratory Animal Science) by JannHau (Editor), Jr., Gerald L. Van Hoosier (Editor). (2004); Animal Modelsof Movement Disorders by Mark LeDoux (Editor), (2005); and Animal Modelsof Cognitive Impairment (Frontiers in Neuroscience) (2006) by Edward D.Levin (Editor), Jerry J. Buccafusco (Editor).

Formulations of the Invention

In addition to comprising ibudilast, a therapeutic formulation of theinvention may optionally contain one or more additional components asdescribed below.

Excipients/Carriers

In addition to ibudilast, the compositions of the invention for treatingprogressive neurodegenerative diseases may further comprise one or morepharmaceutically acceptable excipients or carriers. Exemplary excipientsinclude, without limitation, polyethylene glycol (PEG), hydrogenatedcastor oil (HCO), cremophors, carbohydrates, starches (e.g., cornstarch), inorganic salts, antimicrobial agents, antioxidants,binders/fillers, surfactants, lubricants (e.g., calcium or magnesiumstearate), glidants such as talc, disintegrants, diluents, buffers,acids, bases, film coats, combinations thereof, and the like.

A composition of the invention may include one or more carbohydratessuch as a sugar, a derivatized sugar such as an alditol, aldonic acid,an esterified sugar, and/or a sugar polymer. Specific carbohydrateexcipients include, for example: monosaccharides, such as fructose,maltose, galactose, glucose, D-mannose, sorbose, and the like;disaccharides, such as lactose, sucrose, trehalose, cellobiose, and thelike; polysaccharides, such as raffinose, melezitose, maltodextrins,dextrans, starches, and the like; and alditols, such as mannitol,xylitol, maltitol, lactitol, xylitol, sorbitol (glucitol), pyranosylsorbitol, myoinositol, and the like.

Also suitable for use in the compositions of the invention are potatoand corn-based starches such as sodium starch glycolate and directlycompressible modified starch.

Further representative excipients include inorganic salt or buffers suchas citric acid, sodium chloride, potassium chloride, sodium sulfate,potassium nitrate, sodium phosphate monobasic, sodium phosphate dibasic,and combinations thereof

An ibudilast-containing composition of the invention may also include anantimicrobial agent, e.g., for preventing or deterring microbial growth.Non-limiting examples of antimicrobial agents suitable for the presentinvention include benzalkonium chloride, benzethonium chloride, benzylalcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethylalcohol, phenylmercuric nitrate, thimersol, and combinations thereof.

A composition of the invention may also contain one or moreantioxidants. Antioxidants are used to prevent oxidation, therebypreventing the deterioration of the drug(s) or other components of thepreparation. Suitable antioxidants for use in the present inventioninclude, for example, ascorbyl palmitate, butylated hydroxyanisole,butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, propylgallate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodiummetabisulfite, and combinations thereof.

Additional excipients include surfactants such as polysorbates, e.g.,“Tween 20” and “Tween 80,” and pluronics such as F68 and F88 (both ofwhich are available from BASF, Mount Olive, N.J.), sorbitan esters,lipids (e.g., phospholipids such as lecithin and otherphosphatidylcholines, and phosphatidylethanolamines), fatty acids andfatty esters, steroids such as cholesterol, and chelating agents, suchas EDTA, zinc and other such suitable cations.

Further, a composition of the invention may optionally include one ormore acids or bases. Non-limiting examples of acids that can be usedinclude those acids selected from the group consisting of hydrochloricacid, acetic acid, phosphoric acid, citric acid, malic acid, lacticacid, formic acid, trichloroacetic acid, nitric acid, perchloric acid,phosphoric acid, sulfuric acid, fumaric acid, and combinations thereof.Examples of suitable bases include, without limitation, bases selectedfrom the group consisting of sodium hydroxide, sodium acetate, ammoniumhydroxide, potassium hydroxide, ammonium acetate, potassium acetate,sodium phosphate, potassium phosphate, sodium citrate, sodium formate,sodium sulfate, potassium sulfate, potassium fumerate, and combinationsthereof.

The amount of any individual excipient in the composition will varydepending on the role of the excipient, the dosage requirements of theactive agent components, and particular needs of the composition.Typically, the optimal amount of any individual excipient is determinedthrough routine experimentation, i.e., by preparing compositionscontaining varying amounts of the excipient (ranging from low to high),examining the stability and other parameters, and then determining therange at which optimal performance is attained with no significantadverse effects.

Generally, however, the excipient will be present in the composition inan amount of about 1% to about 99% by weight, preferably from about 5%to about 98% by weight, more preferably from about 15 to about 95% byweight of the excipient. In general, the amount of excipient present inan ibudilast composition of the invention is selected from thefollowing: at least about 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%,45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or even 95% by weight.

These foregoing pharmaceutical excipients along with other excipientsare described in “Remington: The Science & Practice of Pharmacy”, 19thed., Williams & Williams, (1995), the “Physician's Desk Reference”,52.sup.nd ed., Medical Economics, Montvale, N.J. (1998), and Kibbe, A.H., Handbook of Pharmaceutical Excipients, 3.sup.rd Edition, AmericanPharmaceutical Association, Washington, D.C., 2000.

Other Actives

A formulation (or kit) in accordance with the invention may contain, inaddition to ibudilast, one or more additional active agents effective intreating progressive neurodegenerative diseases. Preferably, the activeagent is one that possesses a mechanism of action different from that ofibudilast. Such actives include the combinations for pain listed in USApplication No. 20060160843, as well as the active ingredientsrecognized for treatment for the target diseases. Such activeingredients can be found listed in the FDA's Orange Book, Goodman &Gilman The Pharmacological Basis of Therapeutics, J. Griffith Hardman,L. L. Limbird, A. Gilman, 11th Ed., 2005, The Merck Manual, 18thedition, 2007, and The Merck Manual of Medical Information 2003.

The dosage amounts provided above are meant to be merely guidelines; theprecise amount of a secondary active agent to be administered duringcombination therapy with ibudilast will, of course, be adjustedaccordingly and will depend upon factors such as intended patientpopulation, the particular progressive neuropathic disease symptom orcondition to be treated, potential synergies between the active agentsadministered, and the like, and will readily be determined by oneskilled in the art based upon the guidance provided herein.

Sustained Delivery Formulations

Preferably, the compositions are formulated in order to improvestability and extend the half-life of ibudilast. For example, ibudilastmay be delivered in a sustained-release formulation. Controlled orsustained-release formulations are prepared by incorporating ibudilastinto a carrier or vehicle such as liposomes, nonresorbable impermeablepolymers such as ethylenevinyl acetate copolymers and Hytrel®copolymers, swellable polymers such as hydrogels, or resorbable polymerssuch as collagen and certain polyacids or polyesters such as those usedto make resorbable sutures. Additionally, ibudilast can be encapsulated,adsorbed to, or associated with, particulate carriers. Examples ofparticulate carriers include those derived from polymethyl methacrylatepolymers, as well as microparticles derived from poly(lactides) andpoly(lactide-co-glycolides), known as PLG. See, e.g., Jeffery et al.,Pharm. Res. (1993) 10:362-368; and McGee et al., J. Microencap. (1996).

Delivery Forms

The ibudilast compositions described herein encompass all types offormulations, and in particular, those that are suited for systemic orintrathecal administration. Oral dosage forms include tablets, lozenges,capsules, syrups, oral suspensions, emulsions, granules, and pellets.Alternative formulations include aerosols, transdermal patches, gels,creams, ointments, suppositories, powders or lyophilates that can bereconstituted, as well as liquids. Examples of suitable diluents forreconstituting solid compositions, e.g., prior to injection, includebacteriostatic water for injection, dextrose 5% in water,phosphate-buffered saline, Ringer's solution, saline, sterile water,deionized water, and combinations thereof. With respect to liquidpharmaceutical compositions, solutions and suspensions are envisioned.Preferably, an ibudilast composition of the invention is one suited fororal administration.

In turning now to oral delivery formulations, tablets can be made bycompression or molding, optionally with one or more accessoryingredients or additives. Compressed tablets are prepared, for example,by compressing in a suitable tabletting machine, the active ingredientsin a free-flowing form such as a powder or granules, optionally mixedwith a binder (e.g., povidone, gelatin, hydroxypropylmethyl cellulose),lubricant, inert diluent, preservative, disintegrant (e.g., sodiumstarch glycolate, cross-linked povidone, cross-linked sodiumcarboxymethyl cellulose) and/or surface-active or dispersing agent.

Molded tablets are made, for example, by molding in a suitabletabletting machine, a mixture of powdered compounds moistened with aninert liquid diluent. The tablets may optionally be coated or scored,and may be formulated so as to provide slow or controlled release of theactive ingredients, using, for example, hydroxypropylmethyl cellulose invarying proportions to provide the desired release profile. Tablets mayoptionally be provided with a coating, such as a thin film, sugarcoating, or an enteric coating to provide release in parts of the gutother than the stomach. Processes, equipment, and toll manufacturers fortablet and capsule making are well-known in the art.

Formulations for topical administration in the mouth include lozengescomprising the active ingredients, generally in a flavored base such assucrose and acacia or tragacanth and pastilles comprising the activeingredients in an inert base such as gelatin and glycerin or sucrose andacacia.

A pharmaceutical composition for topical administration may also beformulated as an ointment, cream, suspension, lotion, powder, solution,paste, gel, spray, aerosol or oil.

Alternatively, the formulation may be in the form of a patch (e.g., atransdermal patch) or a dressing such as a bandage or adhesive plasterimpregnated with active ingredients and optionally one or moreexcipients or diluents. Topical formulations may additionally include acompound that enhances absorption or penetration of the ingredientsthrough the skin or other affected areas, such as dimethylsulfoxidembisabolol, oleic acid, isopropyl myristate, and D-limonene, to name afew.

For emulsions, the oily phase is constituted from known ingredients in aknown manner. While this phase may comprise merely an emulsifier(otherwise known as an emulgent), it desirably comprises a mixture of atleast one emulsifier with a fat and/or an oil. Preferably, a hydrophilicemulsifier is included together with a lipophilic emulsifier that actsas a stabilizer. Together, the emulsifier(s) with or withoutstabilizer(s) make up the so-called emulsifying wax, and the waxtogether with the oil and/or fat make up the so-called emulsifyingointment base which forms the oily dispersed phase of creamformulations. Illustrative emulgents and emulsion stabilizers includeTween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glycerylmonostearate and sodium lauryl sulfate.

Formulations for rectal administration are typically in the form of asuppository with a suitable base comprising, for example, cocoa butteror a salicylate.

Formulations suitable for vaginal administration generally take the formof a suppository, tampon, cream, gel, paste, foam or spray.

Formulations suitable for nasal administration, wherein the carrier is asolid, include a coarse powder having a particle size, for example, inthe range of about 20 to about 500 microns. Such a formulation istypically administered by rapid inhalation through the nasal passage,e.g., from a container of the powder held in proximity to the nose.Alternatively, a formulation for nasal delivery may be in the form of aliquid, e.g., a nasal spray or nasal drops.

Aerosolizable formulations for inhalation may be in dry powder form(e.g., suitable for administration by a dry powder inhaler), or,alternatively, may be in liquid form, e.g., for use in a nebulizer.Nebulizers for delivering an aerosolized solution include the AERx®(Aradigm), the Ultravent® (Mallinkrodt), and the Acorn II® (MarquestMedical Products). A composition of the invention may also be deliveredusing a pressurized, metered dose inhaler (MDI), e.g., the Ventolin®metered dose inhaler, containing a solution or suspension of acombination of drugs as described herein in a pharmaceutically inertliquid propellant, e.g., a chlorofluorocarbon or fluorocarbon.

Formulations suitable for parenteral administration include aqueous andnon-aqueous isotonic sterile solutions suitable for injection, as wellas aqueous and non-aqueous sterile suspensions.

Parenteral formulations of the invention are optionally contained inunit-dose or multi-dose sealed containers, for example, ampoules andvials, and may be stored in a freeze-dried (lyophilized) conditionrequiring only the addition of the sterile liquid carrier, for example,water for injections, immediately prior to use. Extemporaneous injectionsolutions and suspensions may be prepared from sterile powders, granulesand tablets of the types previously described.

A formulation of the invention may also be a sustained releaseformulation, such that each of the drug components is released orabsorbed slowly over time, when compared to a non-sustained releaseformulation. Sustained release formulations may employ pro-drug forms ofthe active agent, delayed-release drug delivery systems such asliposomes or polymer matrices, hydrogels, or covalent attachment of apolymer such as polyethylene glycol to the active agent.

In addition to the ingredients particularly mentioned above, theformulations of the invention may optionally include other agentsconventional in the pharmaceutical arts and particular type offormulation being employed, for example, for oral administration forms,the composition for oral administration may also include additionalagents as sweeteners, thickeners or flavoring agents

Kits

Also provided herein is a kit containing at least one combinationcomposition of the invention, accompanied by instructions for use

For example, in instances in which each of the drugs themselves areadministered as individual or separate dosage forms, the kit comprisesibudilast in addition to each of the drugs making up the composition ofthe invention, along with instructions for use. The drug components maybe packaged in any manner suitable for administration, so long as thepackaging, when considered along with the instructions foradministration, clearly indicates the manner in which each of the drugcomponents is to be administered.

For example, for an illustrative kit comprising ibudilast andgabapentin, the kit may be organized by any appropriate time period,such as by day. As an example, for Day 1, a representative kit maycomprise unit dosages of each of ibudilast and gabapentin. If each ofthe drugs is to be administered twice daily, then the kit may contain,corresponding to Day 1, two rows of unit dosage forms of each ofibudilast and gabapentin, along with instructions for the timing ofadministration. Alternatively, if one or more of the drugs differs inthe timing or quantity of unit dosage form to be administered incomparison to the other drug members of the combination, then such wouldbe reflected in the packaging and instructions. Various embodimentsaccording to the above may be readily envisioned, and would of coursedepend upon the particular combination of drugs, in addition toibudilast, employed for treatment, their corresponding dosage forms,recommended dosages, intended patient population, and the like. Thepackaging may be in any form commonly employed for the packaging ofpharmaceuticals, and may utilize any of a number of features such asdifferent colors, wrapping, tamper-resistant packaging, blister paks,dessicants, and the like.

It is to be understood that while the invention has been described inconjunction with preferred specific embodiments, the foregoingdescription as well as the examples that follow are intended toillustrate and not limit the scope of the invention. Other aspects,advantages and modifications within the scope of the invention will beapparent to those skilled in the art to which the invention pertains.

All references mentioned in this application, including any patents,published patent applications, books, handbooks, journal publications,or the FDA Orange Book are hereby incorporated by reference herein, intheir entirety.

EXAMPLES Example 1

A Phase II placebo-controlled, randomized, double-blind study wasconducted using ibudilast in patients with multiple sclerosis. Duringyear 1, patients were treated with 0 mg tid (placebo), 10 mg tid or 20mg tid of ibudilast; during year 2, patients on placebo were randomizedto receive either 10 mg tid or 20 mg tid of ibudilast (patients on 10 mgtid or 20 mg tid during the first year of the study continued on thatdose during the second year). A baseline MRI scan was taken two weeksprior to treatment. Brain volume changes were assessed on an annualbasis with subsequent MRI scans. MRI scans were performed every twomonths of the 2-year period to assess changes in T1 and T2 lesions. Theresults from the first year of the 2-year study are summarized in Table1 below:

TABLE 1 p-value (pbo vs. Outcome Measure 60 mg/day) Annualized relapserate: pbo - 0.8, 60 mg - 0.6 (completers) 0.0752 pbo - 0.9, 60 mg - 0.7(ITT) 0.1106 Time to first relapse (ITT): Median for 60 mg > 1 year0.0438 Median for pbo - 244 days % of subjects exacerbation-free for 1year (ITT): pbo - 41%, 60 mg - 56.1% 0.033 EDSS (% worsened) (ITT):pbo - 30%, 60 mg - 21.4% 0.1771 IDSS (AUC of change from baseline EDSS):pbo: −0.05, 60 mg: −0.24 (completers) 0.0365 pbo: −0.05, 60 mg: −0.16(ITT) 0.1761 Disability progression (worsened ≧1.0 on EDSS for 4 mo)(ITT): pbo - 8%, 60 mg - 4% 0.334

Example 2

A rat animal model for Alzheimer's disease is administered ibudilast andan improvement in cognitive function is achieved for the group ofanimals being administered ibudilast, thereby indicating that this modelcould be effective for the treatment of Alzheimer′ disease in humans.

Example 3

An animal model for progressive multiple sclerosis is administeredibudilast and an improvement in functional outcomes is achieved for thegroup of animals being administered ibudilast, thereby indicating thatthis model could be effective for the treatment progressive multiplesclerosis.

Example 4

An animal model for Parkinson's disease is administered ibudilast and animprovement in locomotion is achieved for the group of animals beingadministered ibudilast, thereby indicating that this model could beeffective for the treatment Parkinson's disease.

Example 5

Table 2 below show that disability progression (greater than or equal toa 1.0 point increase in the Expanded Disability Status Scale (EDSS)score for 4 consecutive months, see Kurtzke J F (1983). “Ratingneurologic impairment in multiple sclerosis: an expanded disabilitystatus scale (EDSS)”. Neurology 33 (11): 1444-52.) was less likely inthose patients receiving MN-166 for 24 months than those receiving thedrug for 12 months (p=0.026). The p-values at 24 Months were: 2 YearActive (pooling of 30 mg and 60 mg dose groups) vs. Placebo to Active(p=0.0264); 60 mg vs. Placebo to Active (p=0.0516), and 30 mg vs.Placebo to Active (p=0.0832). Loss of brain volume on MRI has been shownto correlate with clinical progression and disability in MS patients.These results are consistent with a potential neuroprotective effect ofMN-166 in relapsing MS patients.

TABLE 2 Disability Progression Time Placebo to Active 30 mg 60 mg Period(N = 100) (N = 94) (N = 98) 1 Year     8 (8.0%) 5 (5.3%) 4 (4.1%) 2Years (to 30 mg/d) (to 60 mg/d) 10 (10.6%) 10 (10.2%) 8/51 (15.7%) 13/49(26.5%) p = 0.0832 p = 0.0516 21/100 (21%) 20/194 (10.4%) p = 0.0264

Example 6

Table 3 shows a double-blind analysis of the MRI data from the firstyear of treatment of the two-year Phase II clinical trial of MN-166 inmultiple sclerosis (MS) was conducted. The analysis showed that MN-166decreased the formation of black holes (permanent brain lesions believedto indicate the death of nerves in the brain) on magnetic resonanceimaging (MRI) in MS patients. Data demonstrated that a 60 mg/day dosingregimen of MN-166 significantly reduced the proportion of new T1gadolinium-enhancing or new T2 lesions identified at month two of thestudy that evolved into persistent black holes at month 10 compared toplacebo (RR 0.63, p=0.011). Treatment with a 30 mg/day dosing regimen ofMN-166 showed a trend toward reduced risk of new lesion evolution topersistent black holes compared to placebo (RR 0.735, p=0.074). Of the292 patients who received either placebo (n=100), 30 mg/day of MN-166(n=94) or 60 mg/day of MN-166 (n=98), 72 of the placebo-treatedpatients, 64 of the patients receiving 30 mg/day of MN-166 and 56 of thepatients receiving 60 mg/day of MN-166 had new lesions in month two ofthe study. The proportions of new lesions evolving to persistent blackholes were 0.24, 0.20 and 0.16 in the placebo, 30 mg/day of MN-166 and60 mg/day of MN-166 treatment groups, respectively. The relative risk(RR) for new lesion evolution to persistent black holes wassignificantly lower (RR 0.63, p=0.011) in MS patients treated with 60mg/day of MN-166 and tended to be lower (RR 0.735, p=0.074) in patientstreated with 30 mg/day of MN-166 compared to placebo-treated patients.

The study is the result of randomized, double-blind, placebo-controlledanalysis of year 1 MRI data with MN-166 administration. MRIs werecollected bimonthly during the one year treatment period and werere-evaluated in a double-blind manner for this new analysis. Predefinedendpoints for this evaluation were the rate of evolution of new lesionsto persistent black holes and remyelinated lesions. The predefinedstatistical endpoints were at the rate of evolution of new lesions (NL)to persistent black holes (PBH) and remyelinated lesions (RL). New T1gadolinium-enhancing or new T2 lesions were defined as NL in the firston-study MRI at month 2. Lesions that were hypointense and inactive atmonth 10 were defined as PBH. Hypointense lesions at month 2 or 4 thatwere isointense at month 10 were RL. Relative Risk (RR) of NL evolutionto PBH and RL per patient was analyzed using a general linear model withthe error term from the Poisson distribution.

Overall, the benefits to multiple sclerosis patents of extended (atleast about two years) ibudilast administration include, but are notlimited to, prolongation of time to relapse (by an average of about 130days compared with untreated patients), lessened likelihood forsustained disability progression (a decrease in the rate by about 50%compared with patients treated for less than two years), reduction inbrain volume loss, and reduction in conversion of acute lesions topersistent black holes.

TABLE 3 Reduction of Persistent Black Hole (PBH) Formation TreatmentGroups 30 60 Parameter Placebo mg/day mg/day # Patients w. New Lesionsat Month 2 72 64 56 Mean Proportion of Lesions Evolving to 0.24 0.200.16 PBH Median Proportion of Lesions Evolving 0.17 0.08 0.04 to PBHRelative Risk (for Evolution to PBH) — 0.74 0.63 vs. placebo p Value —0.074 0.011

What is claimed is:
 1. A method of treating a subject diagnosed with amyelopathy comprising administering to the subject a therapeuticallyeffective amount of ibudilast or a pharmaceutically acceptable saltthereof.
 2. The method of claim 1 in which the ibudilast orpharmaceutically acceptable salt thereof is administered for at least 3months.
 3. The method of claim 1 in which the ibudilast orpharmaceutically acceptable salt thereof is administered for at leastsix months.
 4. The method of claim 1 in which the ibudilast orpharmaceutically acceptable salt thereof is administered for at leastone year.
 5. The method of claim 1 in which the ibudilast orpharmaceutically acceptable salt thereof is administered for at leasttwo years.
 6. The method of claim 1 in which the ibudilast orpharmaceutically acceptable salt thereof is administered at least oncedaily.
 7. The method of claim 1 in which the ibudilast orpharmaceutically acceptable salt thereof is administered at least twicedaily.
 8. The method of claim 1 in which the ibudilast orpharmaceutically acceptable salt thereof is administered at least threetimes daily.
 9. The method of claim 1 in which the ibudilast orpharmaceutically acceptable salt thereof is administered orally.
 10. Themethod of claim 1 in which the ibudilast or pharmaceutically acceptablesalt thereof is administered parenterally, enterally, intravenously,intranasally, or sublingually.
 11. The method of claim 1, in which theibudilast or pharmaceutically acceptable salt thereof is administeredthrough an injection.
 12. The method of claim 1, wherein thetherapeutically effective amount of ibudilast or pharmaceuticallyacceptable salt thereof is from about 0.1 mg to about 200 mg per day.13. The method of claim 1, wherein the therapeutically effective amountof ibudilast or pharmaceutically acceptable salt thereof is from about 1mg to about 240 mg per day.
 14. The method of claim 1, wherein thetherapeutically effective amount of ibudilast or pharmaceuticallyacceptable salt thereof is from about 30 mg to about 240 mg per day. 15.The method of claim 1, wherein the therapeutically effective amount ofibudilast or pharmaceutically acceptable salt thereof is from about 30mg to about 180 mg per day.
 16. The method of claim 1, in which thetherapeutically effective amount of ibudilast or pharmaceuticallyacceptable salt thereof is selected from the group consisting of 30mg/day, 60 mg/day, 90 mg/day, or 120 mg/day.
 17. The method of claim 1,in which the therapeutically effective amount of ibudilast orpharmaceutically acceptable salt thereof is 60 mg/day.
 18. The method ofclaim 1, wherein the therapeutically effective amount is administered asa single dose or is divided into multiple dosages.
 19. The method ofclaim 1, wherein the therapeutically effective amount is administered inone, two, or three doses per day.
 20. The method of claim 1, wherein theibudilast or a pharmaceutically acceptable salt thereof is administeredas part of a combination therapy that includes one or more othertherapeutic agents.
 21. The method of claim 20, wherein the one or moreother therapeutic agents is approved and known to have a utility in themyelopathy.
 22. The method of claim 1, wherein the subject is a humansubject.
 23. A method of treating a subject diagnosed with a myelopathycomprising administering to the subject a therapeutically effectiveamount of ibudilast.